Table 1 Different methodologies of risk stratification.
From: High-risk disease in newly diagnosed multiple myeloma: beyond the R-ISS and IMWG definitions
| Â | Serum features | Genomic features | Proposed clinical definition of high risk: | % defined as high risk | Definition of high risk | Outcomes based on risk | Additional important notes |
|---|---|---|---|---|---|---|---|
ISS [3] | Serum β2-microglobulin Serum albumin | None | NAa | 33.6% | ISS stage III: Serum β2-microglobulin >5.5 mg/L | Median OS (months) • Stage I: 62 • Stage II: 45 • Stage III: 29 | B2-microglobulin: indicative of increased tumor burden and declining renal function Serum albumin: driven by inflammatory cytokines such as IL-6 and the bone marrow microenvironment |
R-ISS [2] | LDH Serum β2-microglobulin Serum albumin | del(17p)b t(4;14) t(14;16) | NAc | 10% | ISS stage III and either high-risk CA by iFISH or high LDH | 5-year OS: • Stage 1: 82% • Stage 2: 62% • Stage 3: 40% | Stage 3 patients have a median PFS of 29 months and median OS of 37 months [54] |
IMWG [5] | Serum β2-microglobulin Serum albumin | del(17p)b t(4;14) +1q21 | Median OS <2 years | 20% | ISS II/III and t(4;14) or 17p13 del by iFISH | Median OS: • Low risk: >10 years • Standard risk: 7 years • High risk: 2 years | High-risk group with a 4-year PFS of 12% and OS of just 35% Low-risk group consists of ISS I/II and absence of t(4;14), 17p13 del or +1q21 and age <55 years |
mSMART [55] | LDH Serum β2-microglobulin Serum albumin | Ploidy status t(4;14) t(14;16) t(14;20) t(11;14) t(6/14) del(17p) and p53 deletion deletion 13 gain 1q GEP | NAd | 20% | High-risk genetic Abnormalities • t(14;16); t(14;20); • Del17p or p53 mutation GEP: high-risk signature | Median OS: • High risk: 3 years • Intermediate risk: 4–5 years • Standard risk: 8–10 years | • Trisomies may ameliorate high-risk genetic abnormalities • High plasma cell S-phase also defines high risk: cutoffs vary • Standard risk includes all others including trisomies, t(11;14), and t(6;14) • t(4;14): re-classified as intermediate risk |
EMC92/SYK92 –MMprofiler [30] | None | High-risk survival signature of 92 genese | Median OS <2 years | 18–20% | Two-tiered system of high and standard risk | Reduced OS with HR of 2.06 to 5.23 in validation cohorts amongst the TT2, TT3, APEX, and MRC-IX studies | In multivariate analyses, the signature was proven to be independent of the currently used prognostic factors |
UAMS GEP70 or MyPRS [28] | None | High-risk survival signature of 70 genese | "early disease-related death" | 13–14% | Two-tiered system of high and standard risk | HR for high v standard-risk GEP: • EFS: 3.41 (P = 0.002) • OS: 4.75 (P<0.001) | Standard-risk patients with a 5-year continuous complete remission of 60% vs. 3-year rate of only 20% in those with a high-risk "Early disease-related death" definition not clear in the primary literature |
CoMMpass [19] | LDH | fTP53 mutation λ-chain translocation IGLL5 mutation | Time to progression (TTP) of < 18 months | 20.6% | TTP < 18 months: high-risk TTP >18 months: low risk | Median OS in months: • High risk: 32.8 • ISS III: 54 • Baseline high-risk CA: 65 | TTP 18-month cutoff chosen because time to ASCT was ~6 months and many MM studies define early PD as relapse within 12 months from ASCT |
Serum β2-microglobulin Serum albumin | TP53 inactivation +1q amp | NAg | 6.1% | Biallelic TP53 inactivation or amp of CKS1B (1q21) on the background of ISS stage III | High risk: • Median PFS: 15.4 months • Median OS: 20.7 months | 1q amplification considered ≥ 4 copies LDH values were not universally available preventing the calculation of R-ISS thus ISS and IMWG risk criteria were used | |
Cytogenetics Prognostic Index [9] | None | del(17p) t(4;14) del(1p32) 1q21 gain trisomies 3, 5, and 21 | NA | 11–18% | Prognostic Index >1 defined high riskh | 5-year survival: • High risk: <50% • Int risk: 50–75% • Low risk: >75% | The main objective was to develop and validate a prognostic model based on the seven cytogenetic abnormalities |
